Although most fevers develop in response to pathology in the periphery, the characteristic rise in the level of regulated temperature occurs only through actions of pyrogens on central temperature controls. The major objective in the proposed research is to reach a better understanding of the events and biochemical changes which underlie the central mediation of fever. Using squirrel monkeys, the specificity of i.c.v. infusion of taurine and probenecid in blocking deactivation of endogenous pyrogens and prostaglandin E (PGE) will be tested. These infusions will be used to learn whether central PGE is an obligatory mediator in fever and to determine how central pyrogens are deactivated both normally and in the presence of antipyretics. In related experiments the idea that a central protein mediator is essential to fever will be tested. Our previous observations indicate that the capacity to develop fever remains in man and squirrel monkeys after the primary temperature control in the preoptic/anterior hypothalamic (PO/AH) region is destroyed. To explain this result, presumed to be due to extrahypothalamic sensitivity to pyrogen, sites outside the PO/AH region will be tested for sensitivity to pyrogen before and after the primary temperature control is destroyed. Samples of serum and CSF from febrile man will be used to learn: whether release of central PGE is essential to fever in man; whether the central temperature controls of the squirrel monkey are sensitive enough to circulating human leukocyte pyrogen to be useful as a research model; and whether the fever in patients with Hodgkin's disease comes about through the same central actions which occur in infectious fever. Records of patients taking probenecid will be examined for evidence that blockade of central deactivation of fever mediators can prolong fever in man. Data on patients with neurological disease and abnormal febrile response, especially those with Wernicke's encephalopathy, will also be collected and related to developing knowledge of central mediation of fever.